An integrated method for direct interrogation of sphingolipid homeostasis in the heart and brain tissues of mice through postnatal development up to reproductive senescence

Development of rapid metabolomic methods poised for pathway discovery is expected to facilitate the identification of therapeutic candidates in the metabolomic approach to translational medicine. Using sphingolipid homeostasis as a prototype, we present herein an integrated method to facilitate a fast interrogation of altered sphingolipid (and phospholipid) metabolism associated with perturbed endo-lysosomal functions in mammalian systems. Constructed upon high performance liquid chromatography coupled to mass spectrometry, this method allows semi-quantitative measurements of more than 300 individual species within 20 min. The method was applied to investigate cardiac- and neural-specific developmental changes in sphingolipid regulation from the postnatal stage to reproductive senescence in mice, revealing that endogenous lysobisphosphatidic acids and specific complex glyco-sphingolipids are tightly co-regulated to foster concerted reductions in sphingolipid levels at distinct stages of postnatal development. Our lipidomic data suggest that such changing regulatory patterns in sphingolipid homeostasis is attributed to differential endolysosomal degradation of complex sphingo-lipids, which may be critical in ensuring efficient sphingolipid catabolism and organismal health at each stage of postnatal development. (C) 2018 Elsevier B.V. All rights reserved.